Hes1串扰中枢在肠隐窝Notch-Wnt相互作用中的作用
The Role of the Hes1 Crosstalk Hub in Notch-Wnt Interactions of the Intestinal Crypt
摘要：
Notch通路在决定肠上皮细胞是否采取分泌或吸收表型中起着至关重要的作用。细胞命运特化通过Notch与经典Wnt途径的相互作用来协调。在这里，我们提出了一个新的数学模型的Notch和Wnt途径，其中Hes 1启动子作为一个枢纽的途径串扰。该模型的计算模拟可以帮助理解健康的肠组织是如何维持的，并预测生物化学敲除对细胞命运选择过程的可能后果。化学反应网络理论（CRNT）是一个强大的通用框架，它通过分析底层网络结构的特性来评估我们模型的单稳态或多稳态能力，而无需求助于反应速率的特定参数值或函数形式。CRNT强调了β-连环蛋白在稳定Notch通路和阻尼振荡中的作用，表明Wnt介导的Hes 1启动子作用可以诱导Notch系统从多稳态到单稳态的动态转变。细胞对的时间依赖性模型模拟揭示了Wnt对Notch途径的稳定影响，其中β-连环蛋白和Dsh介导的对Hes 1启动子的作用是塑造亚细胞动力学的关键。在Notch介导的Hes 1转录占主导地位的情况下，存在Notch振荡和维持命运灵活性; Wnt介导的Hes 1转录有利于类似于细胞命运选择的双稳态。因此，细胞可以调节Hes 1启动子的Wnt和Notch介导的控制的比例，以协调细胞命运选择的时间，因为它们迁移通过肠上皮，并受到减少的Wnt刺激。
英文摘要：
The Notch pathway plays a vital role in determining whether cells in the intestinal epithelium adopt a secretory or an absorptive phenotype. Cell fate specification is coordinated via Notch's interaction with the canonical Wnt pathway. Here, we propose a new mathematical model of the Notch and Wnt pathways, in which the Hes1 promoter acts as a hub for pathway crosstalk. Computational simulations of the model can assist in understanding how healthy intestinal tissue is maintained, and predict the likely consequences of biochemical knockouts upon cell fate selection processes. Chemical reaction network theory (CRNT) is a powerful, generalised framework which assesses the capacity of our model for monostability or multistability, by analysing properties of the underlying network structure without recourse to specific parameter values or functional forms for reaction rates. CRNT highlights the role of beta-catenin in stabilising the Notch pathway and damping oscillations, demonstrating that Wnt-mediated actions on the Hes1 promoter can induce dynamical transitions in the Notch system, from multistability to monostability. Time-dependent model simulations of cell pairs reveal the stabilising influence of Wnt upon the Notch pathway, in which beta-catenin- and Dsh-mediated action on the Hes1 promoter are key in shaping the subcellular dynamics. Where Notch-mediated transcription of Hes1 dominates, there is Notch oscillation and maintenance of fate flexibility; Wnt-mediated transcription of Hes1 favours bistability akin to cell fate selection. Cells could therefore regulate the proportion of Wnt- and Notch-mediated control of the Hes1 promoter to coordinate the timing of cell fate selection as they migrate through the intestinal epithelium and are subject to reduced Wnt stimuli.
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